Wednesday, March 14, 2007

MicroRNA

MicroRNA (miRNA) is a short (about 21 to 23 nucleotides) single-stranded RNA molecule that is now recognized as playing an important role in gene regulation – even though the term has been in use only since 2001. It is similar to, but distinct from, another type of short RNA, known as small interfering RNA (siRNA).

Although miRNA and siRNA both have gene regulation functions, there are subtle differences. MiRNA may be slightly shorter than siRNA (which has 20 to 25 nucleotides). MiRNA is single-stranded, while siRNA is formed from two complementary strands. The two kinds of RNA are encoded slightly differently in the genome. And the mechanism by which they regulate genes is slightly different.

MiRNA attaches to a piece of messenger RNA (mRNA) – which is the master template for building a protein – in a non-coding part at one end of the molecule. This acts as a signal to prevent translation of the mRNA into a protein. SiRNA, on the other hand, attaches to a coding region of mRNA, and so it physically blocks translation.

In addition to the Wikipedia articles, here's another handy source of information on miRNA.

There have been several research results reported recently that illustrate some of the important functional roles of miRNA.

MicroRNA and cancer



The importance of gene regulation by miRNA is not trivial. As the following article notes, "microRNAs found in mammals regulate over a third of the human genome, as shown in a 2005 study by the lab of Whitehead Member and Howard Hughes Medical Institute Investigator David Bartel and colleagues." (Reference: MicroRNAs Have Shaped The Evolution Of The Majority Of Mammalian Genes)

Since either overexpression or underexpression of certain genes can cause cancer, it's not surprising that miRNA should have significant cancer-related effects.

MicroRNA helps prevent tumors
Looking to find a promising target for an individual microRNA, Christine Mayr, a postdoctoral researcher in the Bartel lab, picked Hmga2, a gene that is defective in a wide range of tumors.

In these tumors, the protein-producing part of the Hmga2 gene is cut short and replaced with DNA from another chromosome. Biologists have mostly focused on the shortened protein as the possible reason that the cells with this DNA swap became tumors. But this DNA swap removes not only the gene's protein-producing regions but also those areas that don't code for protein. And these non-protein-producing regions contain the elements that microRNAs recognize.

It turns out that in the non-protein-producing region, Hmga2 has seven sites that are complementary to the let-7 microRNA, a microRNA expressed in the later stages of animal development. Mayr wondered whether loss of these let-7 binding sites, and therefore loss of regulation by let-7 of Hmga2, might cause over-expression of Hmga2 that in turn would result in tumor formation.

This turned out to be a very good guess:
Overall, the results highlight a new mechanism for cancer formation. Hmga2, and perhaps certain other genes that are normally regulated by microRNAs, can help give rise to tumors if a mutation in the gene disrupts the microRNA's ability to regulate it.


MicroRNA and stem cells



It's not news to anyone that research into stem cells is a very active area these days. It turns out that miRNA may play a key role in keeping stem cells from differentiating prematurely into normal body cells.

Master Switches Found For Adult Blood Stem Cells
Johns Hopkins Kimmel Cancer Center scientists have found a set of "master switches" that keep adult blood-forming stem cells in their primitive state. Unlocking the switches' code may one day enable scientists to grow new blood cells for transplant into patients with cancer and other bone marrow disorders.

The scientists located the control switches not at the gene level, but farther down the protein production line in more recently discovered forms of ribonucleic acid, or RNA. MicroRNA molecules, once thought to be cellular junk, are now known to switch off activity of the larger RNA strands which allow assembly of the proteins that let cells grow and function.

Since a miRNA molecule can attach itself to a mRNA molecule if there is a match in only about seven consecutive nucleotides, it wouldn't be surprising if one miRNA could regulate the translation of many different proteins. And indeed, this is one of the findings of the research:
To identify the key microRNAs, Georgantas sifted through thousands of RNA pieces with a custom-built, computer software program. Its algorithms let the software, fed data from samples of blood and bone marrow from healthy donors, match RNA pairs. The outcome was a core set of 33 microRNAs that match with more than 1,200 of the larger variety RNA already known to be important for stem-cell maturation.

Just as important for the persistence of a species are stem cells for germline cells – eggs and sperm.

MicroRNA Pathway Essential For Controlling Self-renewal Of Stem Cells
"The findings were interesting to us because they demonstrated that the microRNA pathway is essential for controlling self-renewal or maintenance of two types of stem cells – germline stem cells and somatic stem cells," said Dr. Jin. "In the future, the small RNAs responsible for stem cell regulation could potentially be used to control stem cell functions in vivo and stem cell expansion in vitro."


Editing of microRNA



We have noted that a single miRNA can affect the expression of a large set of genes. It turns out that relatively minor editing of the miRNA after initial transcription can cause it to affect a completely different set of genes:

Killing the messenger RNA — But which one?
Now, a new study led by researchers at The Wistar Institute shows that these microRNAs can undergo a kind of molecular editing with significant physiological consequences. A single substitution in their sequence can redirect these microRNAs to target and silence entirely different sets of genes from their unedited counterparts. Further, errors in the editing can lead to serious health problems.

"What we found was that, in certain cases, edited versions of these microRNAs are being produced that differ from the unedited versions by only a single nucleotide change," says Kazuko Nishikura, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar and senior author on the study. "These edited microRNAs are not encoded in the DNA, which means that at least two versions can being produced by one gene.

If there's one conclusion to be derived from all this recent research, it is that a relative handful of miRNA species – several hundred have been identified so far, compared with 25,000 or so protein-coding genes in humans – are capable of drastically influencing all kinds of cellular processes. That's a lot of "leverage". Applied at the right times and places, miRNA could provide therapies for a large number of diseases. But of course, the ability of a single miRNA to affect so many different genes means that they have to be targeted very, very carefully. It will be interesting to see how this plays out.

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2 Comments:

Anonymous Constantine said...

Thanks for details. I first read about this on http://www.curespinalcordinjury.com/switcher-for-adult-blood-stem-cells However, this is another encouraging step towards cure for people in need.

3/18/2007 02:48:00 AM  
Anonymous Anonymous said...

Check out these great animations on how microRNAs are formed and simulations of therapeutics and diagnostics based on microRNAs
http://www.rosettagenomics.com/?CategoryID=174
http://www.rosettagenomics.com/?CategoryID=171
http://www.rosettagenomics.com/?CategoryID=154

11/15/2007 08:41:00 AM  

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